Acquired Immune Deficiency Syndrome, generally known by its acronym AIDS, is probably the most serious health threat confronting society. It could reach epidemic proportions in the general population before the end of this century. The disease runs a painful and debilitating course and results in the death of its victim. In fact, from diagnosis, the average life span of an AIDS victim is only about three to five years.
HIV-1 also causes a somewhat less serious immunodeficiency syndrome known as AIDS-related complex (ARC). ARC often precedes the onset of AIDS. There are currently many more ARC cases than there are AIDS cases. As the number of infections continues to increase, ARC has, in itself, become a costly and serious health care problem.
AIDS is caused by a virus which has at various times been called human T-cell lymphotropic virus type III (HTLV-III), lymphoadenopathy-associated virus (LAV), and is currently known as human immunodeficiency virus type 1 (HIV-1). Several strains of the virus are known to exist, and it is widely believed that as the virus continues to mutate, many more strains will result.
AIDS results because infection with HIV-1 depletes T helper/inducer lymphocytes (hereinafter referred to as "T cells"). T cells are essential because they control the production of antibodies by the B cells, the maturation of cytotoxic T lymphocytes (killer T cells), the maturation and activity of macrophages and natural killer cells, and, directly and indirectly, numerous other regulator and effector functions of the immune system. Therefore, HIV-1 infection severely compromises the immune response, leaving the victim unable to defend against secondary opportunistic infections. It is often the secondary infections which debilitate the victim and cause death.
In addition to their susceptibility to secondary infections, AIDS victims frequently develop otherwise rare conditions. A large number develop a rare form of skin cancer known as Kaposi's sarcoma.
Infection of a T cell with HIV-1 follows from interaction between an epitope borne by HIV-1 and a receptor site which is located on the T cell surface, known as the CD4 antigen. The epitope on HIV-1 is borne by the envelope glycoprotein gp120 (molecular weight 120,000 daltons). The glycoprotein gp120 is produced when a precursor glycoprotein gp160 is cleaved apart into gp41 (molecular weight 41,000 daltons) and gp120.
HIV-1 is a retrovirus. After the virus has entered the cell, the viral enzyme known as reverse transcriptase transcribes the viral genomic RNA into DNA in the host cell nucleus. The newly synthesized DNA is incorporated into the host cell genome under a variety of activation conditions, and the infected T cell begins to transcribe the new DNA to make copies of messenger RNA and genomic RNA. The viral genomic RNA's are packed with core proteins, reverse transcriptase, and certain other proteins. They are then enveloped by parts of the cellular membrane and budded off from the cell as newly synthesized virions.
These newly synthesized virions can bind to the CD4 antigen on other T cells and enter and infect them. However, HIV-1 can also be transmitted to other T cells through direct cell-to-cell contact or fusion.
Direct cell-to-cell transmission occurs when an infected cell, which expresses the viral gp120 on its surface, binds with the CD4 antigen of an uninfected cell or cells. As a result, the cells fuse and virions can pass to the uninfected cell(s).
Direct cell-to-cell contact and the resulting fusion are a significant source of cellular infection, and may be a major mechanism of T cell destruction in HIV-1 infected individuals. Infected and uninfected cells often fuse in large groups, thereby forming multi-nucleated aggregates known as syncytia. The cell fusion causes the death of cells in the syncytia. See Lifson et al. "Induction of CD4-Dependent Cell Fusion by the HTL-III/LAV Envelope Glycoprotein", Nature 323:725-27 (1986).
Monoclonal antibodies are secreted by hybridoma cells derived from single cell cloning of fused cells. Cells from the monoclonal parent are identical. Accordingly, all the hybridomas of the same clone produce antibodies of the same idiotype which bind to the same epitope of a particular antigen.
Monoclonal antibodies which neutralize HIV-1 are expected to be useful for treatment of HIV-1 infected patients. Such monoclonal antibodies inhibit infection of target cells by free virions and also inhibit syncytium formation between HIV-1-infected cells and other CD4-bearing cells. It is preferred if such monoclonal antibodies can neutralize different strains and isolates of HIV-1.
Passive immunization with neutralizing monoclonal antibodies is expected to be especially effective for uninfected people who are in high-risk groups, and for patients with early-stage infection. Administration of the neutralizing antibodies may either prevent infection by the virus, or may slow the progression of the disease.